TLR4诱导自噬与动脉粥样硬化斑块稳定性的关系以及干预治疗的研究
发布时间：2018-08-11 16:31
【摘要】：脑血管病是威胁人类生命的主要疾病之一。目前很多研究证实动脉粥样硬化易损斑块的破裂和栓子的脱落是引起急性心血管事件及脑卒中的重要原因,颈动脉斑块造成的血管狭窄甚至闭塞、斑块的突然破裂导致急性的动脉阻塞都可以引起缺血性脑卒中。因此,颈动脉斑块的早期识别、斑块稳定性的评价以及干预阻止其进展对于心脑血管病的防治意义重大。第一部分TLR4在动脉粥样硬化斑块形成和进展中的作用机制目的:观察动脉粥样硬化斑块(AP)形成和发展中Toll样受体4(TLR4)表达的变化,探讨TLR4在AP形成和发展的过程中的作用机制。材料与方法:8周龄ApoE(-/-)小鼠20只,适应性喂养1周后,随机分为4组,每组5只,包括对照组、普通饮食组、10周模型组和20周模型组。对照组处死,普通饮食组给予普通饲料喂养10周后处死,10周模型组和20周模型组分别予高脂饮食喂养10周和20周后处死,取血检测血清总胆固醇(TC)、甘油三酯(TG)、氧化型低密度脂蛋白(oxLDL),留取颈动脉和主动脉标本,观察斑块情况,对标本进行HE染色、油红O染色、弹力纤维染色以及天狼猩红染色。并通过免疫组化检测颈动脉斑块巨噬细胞(MOMA-2)、平滑肌肌动蛋白(α-actin)蛋白水平、TLR4、白介素1β(IL-1β)、白介素6(IL-6)、肿瘤坏死因子(TNF-α)的表达。结果:1.普通饲料组TC、TG、oxLDL水平较对照组升高(P0.05);10周模型组较普通饲料组血脂明显升高(P0.05),AP形成。2.20周模型组较对照组和10周模型组血清TC、TG、oxLDL水平升高(P0.05),AP明显增多,斑块脂质成分增加,弹力纤维中断、减少,胶原成分减少,巨噬细胞增加,平滑肌细胞减少。3.20周模型组较对照组和10周模型组颈动脉斑块TLR4、IL-1β、IL-6和TNF-α表达增加(P0.05)。结论:1.ApoE(-/-)小鼠高脂饮食可以成功建立AP动脉的动物模型,且高脂饮食的时间越长,AP越明显。2.ApoE(-/-)小鼠通过高脂饮食建立动脉粥样硬化动物模型后oxLDL水平增高,动脉及斑块炎症因子水平增高,巨噬细胞增多,血管平滑肌细胞减少,胶原合成减少,从而促进斑块的进展,并降低斑块的稳定性。3.apoe(-/-)小鼠随着动脉粥样硬化的加剧,tlr4和炎性因子的表达增加,可能参与促进动脉粥样硬化斑块进展。第二部分tlr4诱导自噬与动脉粥样硬化斑块稳定性的关系目的:观察apoe(-/-)小鼠动脉粥样硬化斑块tlr4表达与自噬的关系,探讨tlr4诱导自噬对动脉粥样硬化斑块(ap)稳定性的影响。方法:8周龄apoe(-/-)小鼠24只,适应性喂养1周后,给予高脂饮食10周后随机分为3组,每组8只,包括lps组、对照组、tak组。lps组给予lps(1mg/kg)腹腔注射,每周2次;tak组给予tak-242(0.3mg/kg)腹腔注射,每周2次;对照组给予相应的等容积的生理盐水腹腔注射,每周2次。三组仍继续高脂饮食,腹腔注射10周后取血检测血清总胆固醇(tc)、甘油三酯(tg)、氧化型低密度脂蛋白(oxldl)。留取颈动脉和主动脉标本,观察斑块情况,对标本进行he染色、油红o染色、弹力纤维染色以及天狼猩红染色。并通过免疫组化检测斑块内巨噬细胞(moma-2)、平滑肌肌动蛋白(α-actin)蛋白水平、toll样受体4(tlr4)、il-1β、il-6、tnf-α的表达。westernblot检测lc3Ⅱ/Ⅰ,beclin-1,p62水平。结果:1.lps组小鼠血清tc、tg、oxldl水平高于对照组和tak组小鼠(p0.05);tak组tg、oxldl水平低于对照组(p0.05)。2.lps组小鼠ap较对照组和tak组巨噬细胞含量(mamo-2免疫组化染色阳性率)增多(p0.05),tak组较对照组小鼠ap巨噬细胞含量减少(p0.05)。lps组较对照组和tak小鼠ap平滑肌细胞含量(α-actin免疫组化染色阳性率)减少(p0.05);tak组较对照组平滑肌含量增加(p0.05)。3.lps组小鼠ap与对照组和tak组比较,tlr4、il-1β、il-6、tnf-α的表达增加(p0.05);tak组较对照组tlr4、il-1β、il-6、tnf-α的表达减少(p0.05)。4.对照组、lps组和tak组小鼠动脉lc3Ⅱ/Ⅰ、p62和beclin-1蛋白表达量有差异(p0.05)。lps组较对照组和tak组lc3Ⅱ/Ⅰ表达增加(p0.001)。lps组较对照组和tak组beclin-1表达增加(p0.001);tak组较对照组beclin-1表达减少(p0.001)。lps组较对照组和tak组p62表达增加(p0.001);tak组较对照组p62表达增加(p0.01)。结论1.lps可以上调aptlr4的表达,tak-242下调tlr4的表达。2.lps上调tlr4表达后,促进炎症因子的分泌,加重脂代谢紊乱,自噬水平明显增高,但p62蛋白水平同时升高,可能lps导致过度自噬而出现自噬功能异常,反而加剧了ap进展和易损性增加。3.tak-242通过下调tlr4的表达,减少巨噬细胞,增加平滑肌细胞的含量,增加斑块的稳定性。第三部分阿托伐他汀及联合普罗布考对tlr4诱导自噬的影响目的:评价阿托伐他汀及联合普罗布考对tlr4诱导的自噬的影响,探讨其抗动脉粥样硬化的作用机制。方法:8周龄apoe(-/-)小鼠24只,适应性喂养1周后,予以高脂饮食10周,再随机分为3组,每组8只,包括对照组、他汀组、联合组。对照组给予等容积超纯水灌胃10周,每天1次;他汀组,高脂饮食的同时给予阿托伐他汀(10mg/kg/d)灌胃10周,每天1次;(3)联合组,换喂食普罗布考饲料,同时给予阿托伐他汀(10mg/kg/d)灌胃10周,每天1次。取血检测血清总胆固醇(tc)、甘油三酯(tg)、氧化型低密度脂蛋白(oxldl)。留取颈动脉和主动脉标本,观察斑块情况,对标本进行he染色、油红o染色、弹力纤维染色和天狼猩红染色。并通过免疫组化检测斑块内巨噬细胞(moma-2)、平滑肌肌动蛋白(α-actin)蛋白水平、toll样受体4(tlr4)、il-1β、il-6、tnf-α的表达。westernblot检测lc3Ⅱ/Ⅰ,beclin-1,p62水平。结果:1.他汀组和联合组tc和oxldl水平较对照组降低,联合组较他汀组oxldl水平降低(p0.05)。2.他汀组和联合组与对照组比较,颈动脉ap弹力纤维较完整,脂质含量减少,胶原含量增加,tlr4、il-1β、il-6、tnf-α的表达减低、平滑肌细胞增加,易损指数降低(p0.05)。联合组较他汀组小鼠颈动脉ap巨噬细胞含量减少,易损指数降低(p0.05)。3.对照组、他汀组和联合组小鼠动脉lc3Ⅱ/Ⅰ、p62和beclin-1蛋白表达量有差异(P0.05)。他汀组和联合组与较对照组动脉Beclin-1表达增加(P0.05);联合组较对照组和他汀组LC3Ⅱ/Ⅰ表达增加,P62表达减少(P0.05)。结论:1.阿托伐他汀可下调TLR4表达,降低血脂,抑制氧化应激和炎症因子的分泌,增加斑块的稳定性。2.联合应用阿托伐他汀和普罗布考较单独应用阿托伐他汀具有更强的抑制氧化应激的作用,减少巨噬细胞含量,适当地增加了自噬水平,发挥更强的抗动脉粥样硬化作用,更有效地增加了斑块的稳定性。
[Abstract]:Cerebrovascular disease is one of the major diseases that threaten human life. Many studies have confirmed that rupture of vulnerable atherosclerotic plaques and loss of embolus are important causes of acute cardiovascular events and stroke. Carotid plaques cause vascular stenosis or occlusion, and sudden rupture of plaques leads to acute arterial obstruction. Therefore, early identification of carotid plaques, evaluation of plaque stability and intervention to prevent their progression are of great significance for the prevention and treatment of cardiovascular and cerebrovascular diseases. Materials and Methods: Twenty eight-week-old ApoE (-/-) mice were randomly divided into four groups after one week of adaptive feeding. Five mice in each group were divided into control group, normal diet group, 10-week model group and 20-week model group. The rats in the 10-week model group and the 20-week model group were sacrificed after 10 and 20 weeks of high-fat diet respectively. The serum total cholesterol (TC), triglyceride (TG), oxidized low-density lipoprotein (oxLDL) and carotid artery and aorta specimens were taken to observe the plaque, HE staining, oil red O staining and elastic fiber staining were performed. The levels of macrophages (MOMA-2), smooth muscle actin (a-actin), TLR4, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor (TNF-a) in carotid plaque were detected by immunohistochemistry. Results: 1. The levels of TC, TG and oxLDL in the normal diet group were higher than those in the control group (P The levels of TC, TG and oxLDL in serum of model group at 2.20 weeks were higher than those of control group and model group at 10 weeks (P 0.05). The levels of AP, lipid components in plaque increased, elastic fibers interrupted, decreased, collagen components decreased, macrophages increased and smooth muscle cells decreased. The levels of TC, TG and oxLDL in model group at 3.20 weeks were higher than those of control group and model group at 10 weeks. The expression of TLR4, IL-1beta, IL-6 and TNF-alpha in carotid artery plaque increased in group A (P 0.05). Conclusion: 1. ApoE (-/-) mice could successfully establish AP artery model by high-fat diet, and the longer the high-fat diet, the more obvious the AP. 2. ApoE (-/-) mice established atherosclerotic animal model by high-fat diet, the oxLDL level increased, arterial and plaque inflammation. 3. Apoe (-/-) mice with increased atherosclerosis, increased expression of TLR4 and inflammatory factors, may participate in the promotion of atherosclerotic plaque progression. Part 2: Tlr4 induction Objective: to observe the relationship between the expression of TLR4 and the stability of atherosclerotic plaque in ApoE (-/-) mice, and to explore the effect of autophagy induced by TLR4 on the stability of atherosclerotic plaque (ap). LPS (1 mg / kg) was injected intraperitoneally twice a week in the LPS group; tak-242 (0.3 mg / kg) was injected intraperitoneally twice a week in the Tak group; and the control group was injected intraperitoneally with the corresponding normal saline of equal volume twice a week in the control group. The three groups continued to eat high-fat diet. After 10 weeks of intraperitoneal injection, the serum total cholesterol was detected. (tc), triglyceride (tg), oxidized low density lipoprotein (oxldl). carotid artery and aorta specimens were taken to observe the plaque condition. he staining, oil red O staining, elastic fiber staining and Sirius scarlet staining were performed. macrophages (moma-2), smooth muscle actin (a-actin) protein level and Toll-like were detected by immunohistochemistry. The expression of receptor 4 (tlr4), interleukin-1 beta, interleukin-6 and TNF-a were detected by Western blot. the levels of tc, TG and oxLDL in serum of mice in LPS group were higher than those in control group and Tak Group (p0.05). the levels of TG and oxLDL in Tak Group were lower than those in control group (p0.05). 2. the contents of macrophages in AP group were higher than those in control group and Tak Group (mamo-2 immunohistochemical staining positive). Sex rate increased (p0.05), Tak group compared with the control group AP macrophage content decreased (p0.05). LPS group compared with the control group and Tak mice AP smooth muscle cell content (a-actin immunohistochemical staining positive rate) decreased (p0.05); Tak group compared with the control group smooth muscle content increased (p0.05). 3. LPS group mice AP compared with the control group and Tak group, tlr4, IL-1 beta, il-6, TNF-a. The expression of tlr4, IL-1 beta, IL-6 and TNF-a in the Tak Group was lower than that in the control group (p0.05). 4. the expression of lc3ii / _, p62 and beclin-1 in the arteries of the LPS group and the Tak Group were different (p0.05). the expression of lc3ii / _in the LPS group was higher than that in the control group and the Tak Group (p0.001). the expression of beclin-1 in the LPS group was higher than that in the control group and the Tak Group (p0.001). The expression of beclin-1 in Group K was lower than that in control group (p0.001). the expression of p62 in LPS group was higher than that in control group and Tak Group (p0.001). the expression of p62 in Tak Group was higher than that in control group (p0.01). conclusion 1. LPS can up-regulate the expression of aptlr4, and tak-242 can down-regulate the expression of tlr4. 2. LPS can up-regulate the expression of tlr4, promote the secretion of inflammatory factors, aggravate the disorder of lipid metabolism, and significantly increase the level of autophagy. High levels of p62 protein may lead to excessive autophagy and autophagy dysfunction, but aggravate the progress and vulnerability of ap. 3. tak-242 down-regulates the expression of tlr4, reduces macrophages, increases the content of smooth muscle cells, and increases the stability of plaque. part three: atorvastatin and probucol combined with TLR4 AIM: To evaluate the effect of atorvastatin and probucol on autophagy induced by TLR4 and explore the mechanism of its anti-atherosclerosis effect. METHODS: Twenty-four apoE (-/-) mice aged 8 weeks were fed with high-fat diet for 10 weeks, and then randomly divided into three groups, eight in each group, including control group, statin group and combined group. The control group was given isovolumetric ultrapure water once a day for 10 weeks, while the statin group was given atorvastatin (10mg/kg/d) for 10 weeks, once a day; (3) the combined group was given probucol feed, and atorvastatin (10mg/kg/d) for 10 weeks, once a day. Carotid artery and aorta specimens were taken to observe the plaque. he staining, o il red O staining, elastic fiber staining and Sirius red staining were performed. the levels of macrophages (moma-2), smooth muscle actin (a-actin) protein, Toll-like receptor 4 (tlr4), IL-1 beta, il-6, TN in the plaque were detected by immunohistochemistry. The levels of TC and oxLDL in statin group and combined group were lower than those in control group, and the levels of oxLDL in combined group were lower than those in statin group (p0.05). 2. compared with the control group, the elastic fibers of carotid artery AP in statin group and combined group were more intact, the content of lipid decreased, the content of collagen increased, tlr4, IL-1 beta, and IL-1 beta. Compared with statin group, the content of AP macrophages in carotid artery decreased, and the vulnerability index decreased (p0.05). 3. the expression of LC3 II / i, p62 and beclin-1 in arteries of control group, statin group and combination group were different (p0.05). statin group and combination group were compared with control group. Compared with the control group and statin group, the expression of LC3 II/I increased and the expression of P62 decreased in the combined group (P 0.05). Conclusion: 1. Atorvastatin can down-regulate the expression of TLR4, reduce blood lipid, inhibit the secretion of oxidative stress and inflammatory factors, and increase the stability of plaque. 2. Atorvastatin combined with probucol is more effective than alone. Atorvastatin can inhibit oxidative stress, decrease macrophage content, increase autophagy level, exert stronger anti-atherosclerosis effect, and increase plaque stability more effectively.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R543.5
本文编号：2177582
[Abstract]:Cerebrovascular disease is one of the major diseases that threaten human life. Many studies have confirmed that rupture of vulnerable atherosclerotic plaques and loss of embolus are important causes of acute cardiovascular events and stroke. Carotid plaques cause vascular stenosis or occlusion, and sudden rupture of plaques leads to acute arterial obstruction. Therefore, early identification of carotid plaques, evaluation of plaque stability and intervention to prevent their progression are of great significance for the prevention and treatment of cardiovascular and cerebrovascular diseases. Materials and Methods: Twenty eight-week-old ApoE (-/-) mice were randomly divided into four groups after one week of adaptive feeding. Five mice in each group were divided into control group, normal diet group, 10-week model group and 20-week model group. The rats in the 10-week model group and the 20-week model group were sacrificed after 10 and 20 weeks of high-fat diet respectively. The serum total cholesterol (TC), triglyceride (TG), oxidized low-density lipoprotein (oxLDL) and carotid artery and aorta specimens were taken to observe the plaque, HE staining, oil red O staining and elastic fiber staining were performed. The levels of macrophages (MOMA-2), smooth muscle actin (a-actin), TLR4, interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), tumor necrosis factor (TNF-a) in carotid plaque were detected by immunohistochemistry. Results: 1. The levels of TC, TG and oxLDL in the normal diet group were higher than those in the control group (P The levels of TC, TG and oxLDL in serum of model group at 2.20 weeks were higher than those of control group and model group at 10 weeks (P 0.05). The levels of AP, lipid components in plaque increased, elastic fibers interrupted, decreased, collagen components decreased, macrophages increased and smooth muscle cells decreased. The levels of TC, TG and oxLDL in model group at 3.20 weeks were higher than those of control group and model group at 10 weeks. The expression of TLR4, IL-1beta, IL-6 and TNF-alpha in carotid artery plaque increased in group A (P 0.05). Conclusion: 1. ApoE (-/-) mice could successfully establish AP artery model by high-fat diet, and the longer the high-fat diet, the more obvious the AP. 2. ApoE (-/-) mice established atherosclerotic animal model by high-fat diet, the oxLDL level increased, arterial and plaque inflammation. 3. Apoe (-/-) mice with increased atherosclerosis, increased expression of TLR4 and inflammatory factors, may participate in the promotion of atherosclerotic plaque progression. Part 2: Tlr4 induction Objective: to observe the relationship between the expression of TLR4 and the stability of atherosclerotic plaque in ApoE (-/-) mice, and to explore the effect of autophagy induced by TLR4 on the stability of atherosclerotic plaque (ap). LPS (1 mg / kg) was injected intraperitoneally twice a week in the LPS group; tak-242 (0.3 mg / kg) was injected intraperitoneally twice a week in the Tak group; and the control group was injected intraperitoneally with the corresponding normal saline of equal volume twice a week in the control group. The three groups continued to eat high-fat diet. After 10 weeks of intraperitoneal injection, the serum total cholesterol was detected. (tc), triglyceride (tg), oxidized low density lipoprotein (oxldl). carotid artery and aorta specimens were taken to observe the plaque condition. he staining, oil red O staining, elastic fiber staining and Sirius scarlet staining were performed. macrophages (moma-2), smooth muscle actin (a-actin) protein level and Toll-like were detected by immunohistochemistry. The expression of receptor 4 (tlr4), interleukin-1 beta, interleukin-6 and TNF-a were detected by Western blot. the levels of tc, TG and oxLDL in serum of mice in LPS group were higher than those in control group and Tak Group (p0.05). the levels of TG and oxLDL in Tak Group were lower than those in control group (p0.05). 2. the contents of macrophages in AP group were higher than those in control group and Tak Group (mamo-2 immunohistochemical staining positive). Sex rate increased (p0.05), Tak group compared with the control group AP macrophage content decreased (p0.05). LPS group compared with the control group and Tak mice AP smooth muscle cell content (a-actin immunohistochemical staining positive rate) decreased (p0.05); Tak group compared with the control group smooth muscle content increased (p0.05). 3. LPS group mice AP compared with the control group and Tak group, tlr4, IL-1 beta, il-6, TNF-a. The expression of tlr4, IL-1 beta, IL-6 and TNF-a in the Tak Group was lower than that in the control group (p0.05). 4. the expression of lc3ii / _, p62 and beclin-1 in the arteries of the LPS group and the Tak Group were different (p0.05). the expression of lc3ii / _in the LPS group was higher than that in the control group and the Tak Group (p0.001). the expression of beclin-1 in the LPS group was higher than that in the control group and the Tak Group (p0.001). The expression of beclin-1 in Group K was lower than that in control group (p0.001). the expression of p62 in LPS group was higher than that in control group and Tak Group (p0.001). the expression of p62 in Tak Group was higher than that in control group (p0.01). conclusion 1. LPS can up-regulate the expression of aptlr4, and tak-242 can down-regulate the expression of tlr4. 2. LPS can up-regulate the expression of tlr4, promote the secretion of inflammatory factors, aggravate the disorder of lipid metabolism, and significantly increase the level of autophagy. High levels of p62 protein may lead to excessive autophagy and autophagy dysfunction, but aggravate the progress and vulnerability of ap. 3. tak-242 down-regulates the expression of tlr4, reduces macrophages, increases the content of smooth muscle cells, and increases the stability of plaque. part three: atorvastatin and probucol combined with TLR4 AIM: To evaluate the effect of atorvastatin and probucol on autophagy induced by TLR4 and explore the mechanism of its anti-atherosclerosis effect. METHODS: Twenty-four apoE (-/-) mice aged 8 weeks were fed with high-fat diet for 10 weeks, and then randomly divided into three groups, eight in each group, including control group, statin group and combined group. The control group was given isovolumetric ultrapure water once a day for 10 weeks, while the statin group was given atorvastatin (10mg/kg/d) for 10 weeks, once a day; (3) the combined group was given probucol feed, and atorvastatin (10mg/kg/d) for 10 weeks, once a day. Carotid artery and aorta specimens were taken to observe the plaque. he staining, o il red O staining, elastic fiber staining and Sirius red staining were performed. the levels of macrophages (moma-2), smooth muscle actin (a-actin) protein, Toll-like receptor 4 (tlr4), IL-1 beta, il-6, TN in the plaque were detected by immunohistochemistry. The levels of TC and oxLDL in statin group and combined group were lower than those in control group, and the levels of oxLDL in combined group were lower than those in statin group (p0.05). 2. compared with the control group, the elastic fibers of carotid artery AP in statin group and combined group were more intact, the content of lipid decreased, the content of collagen increased, tlr4, IL-1 beta, and IL-1 beta. Compared with statin group, the content of AP macrophages in carotid artery decreased, and the vulnerability index decreased (p0.05). 3. the expression of LC3 II / i, p62 and beclin-1 in arteries of control group, statin group and combination group were different (p0.05). statin group and combination group were compared with control group. Compared with the control group and statin group, the expression of LC3 II/I increased and the expression of P62 decreased in the combined group (P 0.05). Conclusion: 1. Atorvastatin can down-regulate the expression of TLR4, reduce blood lipid, inhibit the secretion of oxidative stress and inflammatory factors, and increase the stability of plaque. 2. Atorvastatin combined with probucol is more effective than alone. Atorvastatin can inhibit oxidative stress, decrease macrophage content, increase autophagy level, exert stronger anti-atherosclerosis effect, and increase plaque stability more effectively.
【学位授予单位】：天津医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R543.5
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